Dr Rosen is Pediatric and Adolescent Gynecology Fellow, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI.
Dr Quint is Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI.
Studies have shown that 1 in 5 women who consult their doctor for heavy or prolonged bleeding during their periods actually have an underlying bleeding disorder.
A 16-year-old girl presents to your office complaining of heavy menstrual cycles since menarche. Her cycles last 15 days on average and she changes her pads every hour on the heaviest days. She often passes large clots and misses at least 1 day of school per cycle. Should you be concerned?
Studies have shown that 1 in 5 women who consult their doctor for heavy or prolonged bleeding during their periods actually have an underlying bleeding disorder.1 The proportion is postulated to be even higher for adolescents.2 A study that looks at all admissions to a children’s hospital over a 9-year time period for acute menorrhagia in adolescence found a primary coagulation disorder in almost 20% of 59 adolescent patients and in 50% of those who presented at menarche. In this study, 25% of the adolescents had a hemoglobin of less than 10 g/100ml on admission, and one-third required a transfusion.3
Bleeding disorders can have major downstream health consequences, including iron deficiency anemia, the need for blood transfusions, increased bleeding during and after surgeries, postpartum bleeding, poor wound healing, and an increased risk of hysterectomy. A survey from the Centers for Disease Control and Prevention (CDC) reported that women with bleeding disorders are also more likely to have 1 or more of several other gynecologic conditions, including hemorrhagic ovarian cysts, endometriosis, polyps, and fibroids.4
Early recognition of a bleeding disorder can have a major impact on a patient’s quality of life. Because ob/gyns are often the first to evaluate menstrual bleeding concerns it is extremely important that they have a comprehensive understanding of appropriate screening measures and treatment options for patients with suspected bleeding disorders.
Von Willebrand disease
In a 2002 CDC survey of 376 ob/gyns across the United States, only 4% of respondents claimed that they would consider von Willebrand disease (vWD) as the cause of heavy menstrual bleeding (HMB) in a woman of reproductive age, and only 6% of respondents would consider it in a girl near menarche.5 The responses substantially improved in a similar survey conducted in 2012, when 39% reported that they would consider a bleeding disorder as causing HMB in women of reproductive age and 77% would consider this an option in adolescents.6
vWD is the most common inherited bleeding disorder, with an overall prevalence of 0.6% to 1.3%.7 It has an autosomal-dominant inheritance pattern and is caused by a missing or defective von Willebrand factor (vWF), a clotting protein. vWF binds to both factor VIII, a key clotting protein, and to platelets, to form a platelet plug during the clotting process. There are 3 types of vWD, which vary in severity. Type 1 is the most common (60% to 80% of cases) and is relatively mild. The disease is diagnosed more often in females because of the presentation of HMB - according to a systematic review of 11 studies involving 988 women, the prevalence of vWD in women presenting with HMB was reported to be as high as 13% to 24%.8 Research has suggested that as many as 9 of 10 individuals with vWD remain undiagnosed.9 (For a full discussion of vWD, see the May 2017 issue of Contemporary OB/GYN.)
Platelet function defects
Platelet dysfunction leads to impaired clot formation and includes disorders of platelet adhesion, aggregation, secretion, or procoagulant activity. Acquired platelet dysfunction is common with use of certain medications, such as aspirin. Data on the prevalence of platelet dysfunction in women presenting with HMB are very limited, as it is very difficult to diagnose due to the need for highly complex and specialized testing. Some studies, however, have shown a prevalence upwards of 47% in women with HMB and a higher incidence among African- American women than Caucasians.10
Coagulation factor deficiencies
Women with coagulation factor deficiencies have low levels of a specific blood protein, such as factors I (fibrinogen), II, V, VII, X, XI, and XIII. A deficiency in any of these factors makes it difficult for a blood clot to form. The exact prevalence of these disorders is unknown, but deficiencies of this type are relatively rare and are estimated to occur in approximately 1 out of 500,000 individuals.11 The most common factor deficiencies involve factors VIII (Hemophilia A) and IX (Hemophilia B).
Hemophiliac disorders represent the most common severe inherited bleeding conditions. Hemophilia largely affects males, as it is an X linked genetic condition. Females are carriers, but may also exhibit mild to severe bleeding symptoms as carriers. Hemophilia A (a deficiency in clotting factor VIII) affects approximately 1 in 10,000 individuals, and Hemophilia B (a deficiency in clotting factor IX) affects approximately one in 50,000. An estimated 10% to 57% of women with HMB are hemophilia carriers.2
As previously noted, gynecologists are often tasked with screening for bleeding disorders due to the complaint of HMB. According to the American College of Obstetricians and Gynecologists (ACOG), an adolescent who reports even 1 of the following should be further evaluated for a bleeding disorder: menses greater than 7 days with a flooding/gushing sensation or bleeding through a pad/tampon in 2 hours; history of anemia; family history of a bleeding disorder; or history of a bleeding disorder after a monostatic challenge (tooth extraction, surgery, delivery).12 (Figures 1 and 2)
Several qualitative and quantitative methods can be used to screen for HMB to accurately diagnose an underlying bleeding disorder. Although the alkaline hematin test is considered the gold standard for measuring menstrual blood loss (MBL), it is complex and used, primarily, in research settings. The method involves pummeling used feminine hygiene products in a solution and measuring the resulting hematin absorbance against calibration curves. The Pictorial Blood Assessment Chart (PBAC) uses diagrams with light, moderate, and heavily soaked pads and tampons to evaluate how much bleeding a patient is experiencing during her cycle. (Figure 3) A total score of more than 100 per cycle correlates to HMB.13
A 2014 European study of 165 women demonstrated a more practical method for estimating MBL through use of a calculated questionnaire score that compares to a baseline of healthy women of childbearing age. Like the PBAC, the MBL score calculates a numerical value based on the number of pads or tampons used, which is then used to estimate blood loss.14 The menstrual cup, a device that catches menstrual flow inside the vagina and is used by women as a hygiene product, can also be used as a quick and fairly reliable method of assessing blood loss by describing how full the cup is and how many times it is changed per day. Each cup can hold 30 mL of blood, and it is a product used by many adolescents. Questionnaires may also be used as screening tools to estimate blood loss. (Figure 4)
In both adolescents and adults, once a positive bleeding screen has been confirmed, initial tests to order include a complete blood count (CBC), platelet count, prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen. If bleeding history is strong or anemia is present in the absence of fibroids, specific tests for vWD disease may be ordered, including von Willebrand-ristocetin cofactor activity, vWF antigen, and factor VIII (often ordered as a von Willebrand panel).15 It should be noted that no single test alone can reliably diagnose vWD. A hematologist usually interprets test results in conjunction with a gynecologist. Iron studies can also be considered with heavy bleeding, even in the absence of anemia.
Some of the hematological test results may be affected by several variables, including stress, systemic inflammation, anemia, pregnancy, oral contraceptives (OC), time of the menstrual cycle, sample processing, and quality of the laboratory. Ideally, any vWD tests should be performed before starting hormonal management and, because of potential confounders repeat testing may be necessary to establish a definitive diagnosis. Because of these and other factors, the mean time to diagnose a bleeding disorder is on the order of 9 years.
Treatment of acute bleeding can certainly overlap in patients with and without bleeding disorders. Figure 5 lists common medications used, both hormonal and non-hormonal, as well as surgeries available for management of acute bleeding.16,17
In women with vWD, the recommendation for first-line treatment of acute abnormal uterine bleeding is desmopressin (DDAVP) and tranexamic acid (TA) together for 2 to 3 days, followed by TA alone for 3 to 4 days.16 DDAVP is a synthetic derivative of the antidiuretic hormone vasopressin and works by stimulating the release of vWF from endothelial cells. It can be given intravenously, subcutaneously, intranasally or orally. Antifibrinolytics such as TA inhibit conversion of plasminogen to plasmin, which then inhibits fibrinolysis and helps to stabilize clots. TA was approved for oral treatment of HMB by the US Food and Drug Administration (FDA) in 2009. Of note, there are theoretical risks of increased VTE if taking TA while on hormonal contraception.
Exogenous coagulation factors in the form of vWF concentrate or a factor VIII–vWF concentrate (HUMATE P) can also be infused to normalize vWF and factor VIII levels in the blood.16
Treatment for acute abnormal uterine bleeding in patients with a platelet function disorder should include platelet transfusion as first-line therapy. These patients should also avoid nonsteroidal anti-inflammatory drugs and other drugs that affect platelet aggregation.17 In the setting of factor deficiencies, factors that are missing or diminished should first be infused and consideration given to use of fibrinogen as an adjunct option. For hemophilia A carriers, DDAVP can be used. Infusions of clotting factor concentrates may also be necessary for both hemophilia A and B. Lastly, TA can be useful for treatment of acute bleeding with platelet dysfunction (Figure 6)16,17
Maintenance therapy for women with bleeding disorders includes evaluation of several factors, such as patient compliance, preference, cost, results of prior therapy (if applicable), insurance coverage, current medication use, and existence of any preexisting medical conditions. Both hormonal and non-hormonal options are available and are often used together. A 2010 study looked at the Mirena IUD for management of heavy menstrual bleeding in women with inherited bleeding disorders and found significant benefit in its use as a long-term treatment.18 Initiating or adding TA to a hormonal treatment regimen has also been shown to reduce HMB by 34% to 65% in patients with bleeding disorders.19 If using a combined hormonal treatment, such as OCs, the patch, or the ring, continuous or extended use is recommended to reduce menstrual bleeding.
In obstetrics, women with bleeding disorders may actually benefit from the hypercoagulable state of pregnancy, which increases concentrations of several coagulation factors and fibrinogen. Nevertheless, women with bleeding disorders remain at increased risk of multiple complications as they often do not achieve the same level of clotting factors as others.20 (Figure 7)
With respect to preconception counseling women suspected of having a bleeding disorder, or of being carriers, should undergo diagnostic testing prior to pregnancy to optimize pregnancy management. If a woman is a carrier of a certain disorder, pre-implantation genetic testing can be considered and in vitro fertilization may be used to implant only those embryos without the disorder. Another aspect of preconception care includes immunization against hepatitis A and B for those likely to require a blood transfusion.
Regarding early pregnancy, there are several case reports and series documenting an increased risk of miscarriage and placental abruption in women with certain bleeding disorders, such as a Factor XIII or fibrinogen deficiency,20 and during labor there is an increased risk of spinal/epidural hematomas. A fetus can also potentially be at a substantial risk of bleeding complications during birth. Invasive intrapartum monitoring techniques (eg, fetal scalp electrode) should be avoided in pregnancies with a potentially affected fetus as intracranial hemorrhage may occur.
Most experts agree that women with bleeding disorders can have a safe vaginal delivery and that a cesarean delivery should be reserved for standard reasons. A recent study on babies with hemophilia found no difference in the rate of fetal intracranial hemorrhage based on mode of delivery.21 Vacuum and forceps deliveries, however, should be avoided due to the higher risk of intracranial hemorrhage.
Women with bleeding disorders are at increased risk of both antepartum and postpartum hemorrhage. Risk of postpartum hemorrhage in women with vWD is 50% higher than in those without a bleeding disorder.22 Because women with bleeding disorders are known to present with delayed hemorrhage once estrogen levels decrease in the postpartum period, some physicians will offer prophylactic therapy to cover the immediate postpartum period. DDAVP, for example, can be used to raise vWF levels for this purpose.
Bleeding disorders are both prevalent and serious enough in obstetrical and gynecologic practice that the generalist ob/gyn should be fully aware of their existence, potential downstream consequences, and treatment options. These disorders can significantly impact quality of life, but unfortunately, many women remain undiagnosed and untreated due to a lack of familiarity on the part of both patients and the health care professionals they rely on. Ob/gyns should heighten their understanding and appreciation of the importance and implications of bleeding disorders to consistently deliver the best care possible for their patients.
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